Venlafaxine in the Treatment of Depression: Practical Considerations

Venlafaxine in the Treatment of Depression: Practical Considerations

Effexor) is a novel antidepressant recently released to the American market. Its entry into the antidepressant market has been much heralded. The lay
press has described the drug as "

Prozac
with a punch," and many patients were asking for it long
before it was available. As the hoopla settles down, we are learning
that

venlafaxine is a potentially important
drug with both advantages and disadvantages over other available

antidepressants, including the

selective
serotonin reuptake inhibitors (SSRIs).

Pharmacology

Venlafaxine is a phenylethylamine antidepressant that, unlike
the SSRIs, strongly inhibits the reuptake of both serotonin and
norepinephrine. At high doses (>375 mg per day), it also appears
to impact the reuptake of dopamine and this may be clinically
significant in the treatment of depression. Venlafaxine's mechanism
of action perhaps most closely resembles that of the tricyclics
that also interfere with the reuptake of monamine neurotransmitters.
However, unlike the tricyclics, venlafaxine has no significant
affinity for muscarinic, alpha adrenergic or histaminergic receptors.

In addition to the monamine selectivity of venlafaxine, two other
pharmacological parameters may distinguish venlafaxine from most
other antidepressants. The first is that venlafaxine is rather
weakly bound to protein. While the tricyclics and SSRIs tend to
be highly bound to serum and tissue protein at levels of 85 percent
or more, venlafaxine is only about 30 percent bound to albumin.
As a result, venlafaxine is less likely to be displaced by other
tightly protein-bound drugs such as oral contraceptives and phenytoin
(Dilantin).

Another distinguishing pharmacological parameter of venlafaxine
is that it appears to cause the rapid down-regulation of the beta
adrenergic-linked cAMP system. Isoprotere-nol (Isaprel) typically
induces an increase in cyclic adenosine monophosphate (cAMP) in
control animals, and chronic administration with antidepressants
tends to inhibit cAMP production. The decreased sensitivity of
the beta adrenergic system appears to be associated with onset
of clinical antidepressant effects. At this time, venlafaxine
is the only antidepressant known to produce this down-regulation
of beta adrenergic-linked cAMP production in the rat pineal after
a single dose. The clinical significance of this finding, if replicated,
may be that venlafaxine would be expected to have an earlier onset
of action. In fact, a number of premarketing controlled studies
have suggested that venlafaxine may have significant antidepressant
effects in the first two weeks of treatment (Schweizer and coworkers
1991; Khan 1991, Guelfi and coworkers 1992; Mendels and colleagues
1993). However, several antidepressants have looked promising
as more rapidly acting agents in the premarketing literature only
to be disappointing when further studied. At present it is unclear
whether venlafaxine will distinguish itself as an antidepressant
that truly acts more rapidly or whether it will follow suit with
other antidepressants that have made this claim.

Efficacy in Major Depression

The efficacy of venlafaxine in the treatment of major depression
has been established by a number of placebo-controlled studies.

In a study by

Schweizer and colleagues (1991),
90 percent of 224 outpatients treated with venlafaxine for major
depression showed moderate to marked improvement with venlafaxine
treatment compared to 79 percent of patients taking

imipramine
(Tofranil) and 53 percent of patients on placebo. Endpoint analysis
suggested that only venlafaxine was statistically superior to
placebo because of the higher attrition rate of the imipramine-treated
group (25 percent versus 16 percent in the venlafaxine-treated
group). In an earlier six-week study, Schweizer and colleagues
(1989) compared venlafaxine and placebo in 44 outpatients with
major depression. They found that venlafaxine at doses up to 375
mg per day was more than twice as likely to induce a marked improvement
in depressive symptoms than placebo.

Cunningham
and colleagues (1994) found that treatment with venlafaxine for
six weeks in 225 patients with major depression resulted in more
significant improvement in the venlafaxine-treated group (72 percent)
than either

trazodone (Desyrel) (60 percent)
or placebo-treated groups. Venlafaxine also produced more improvement
in the retardation and cognitive disturbance scales of the Hamilton
Depression Rating Scale.

Mendels and colleagues
studied 312 depressed outpatients on doses ranging from 25 to
200 mg per day and found that the higher-dose group had a significantly
better response rate on venlafaxine than placebo and that the
lower-dose groups did not show a robust antidepressant effect.
Finally,

Khan demonstrated that venlafaxine was significantly
better than placebo at doses ranging from 75 mg per day to 375
mg per day in 93 depressed outpatients treated for six weeks.
Inpatients with more severe depressive episodes represent an important
target population for antidepressant therapy. Thus far, two studies
have suggested venlafaxine may be useful in severely depressed
inpatients with melancholia.

Guelfi and associates
found venlafaxine, rapidly titrated up to the maximum dose of
375 mg per day, was superior to placebo in this population within
the first week of treatment. In a more recently published study,

Clerc and colleagues (1994) found venlafaxine superior to fluoxetine
in the treatment of 68 melancholic inpatients at four and six
weeks. However, this was not a placebo-controlled study, and the
data must be considered preliminary.

Maintenance protocols have demonstrated the expected finding that
venlafaxine is also effective in preventing relapse in patients
with

recurrent depression.

Entsuah
and colleagues (1993) reported on 396 patients who responded to
acute treatment with an antidepressant and were maintained on
either placebo, imipramine, trazodone or venlafaxine for one year.
Venlafaxine was superior to placebo and at least as effective
as the other active compounds in preventing relapse of depression
at six and 12 months.

Another possible indication for venlafaxine is in the treatment
of

refractory depression. Given
its effect on both serotonin and norepinephrine, venlafaxine may
be a reasonable option for treating patients who have not responded
to other treatments.

Nierenberg and colleagues
(1993) studied venlafaxine in patients who had not responded to
either three adequate antidepressant trials of different classes
or two trials and one course of electroconvulsive therapy (ECT).
In addition, patients also were required to have failed at least
one attempt at augmentation. Of 82 patients who met criteria for
major depression, about one-third of these refractory patients
were judged to be full responders to venlafaxine treatment (Hamilton
Depression Rating Scale score < 8). Approximately 80 percent
of these responders maintained their improvement for at least
six months. This was an open-label study, however, and double-blind
studies are needed to confirm the findings.